Duration Of Severe Neutropenia Research Articles

Prognostic Factors for Survival Using a Clinical Severity Staging System Among Patients With Acute Invasive Fungal Sinusitis

Despite the aggressive progression of fulminant acute invasive fungal sinusitis (AIFS), data on prognostic factors have been disparate, hindering the development of a staging system. A composite staging system may improve prognostication for patient counseling and conduct of clinical research. To identify prognostically important factors in AIFS and to incorporate the factors into a comprehensive Functional Severity Staging System and Clinical Severity Staging System. This retrospective cohort study included adult patients diagnosed with pathology-proven AIFS from June 1, 1992, to December 31, 2022, at Washington University Medical Center and Barnes-Jewish Hospital, a tertiary care center in St Louis, Missouri. Data were analyzed from April to July 2023. Sequential sequestration and conjunctive consolidation was used to develop a composite staging system to predict 6-month overall survival. Of 71 patients with pathology-proven AIFS over the 30-year period, the median (range) age of the cohort was 56 (19-63) years, and there were 47 (66%) male patients. The median (range) follow-up time was 2 (0-251) months. There were 28 patients alive within 6 months, for a 39% survival rate. Symptoms, comorbidity burden, and presence and duration of severe neutropenia were associated with 6-month survival and were consolidated into a 3-category Clinical Severity Staging System with 6-month survival of 75% for stage A (n = 16), 41% for stage B (n = 27), and 18% for stage C (n = 28). The discriminative power of the composite staging system was moderate (C statistic, 0.63). This cohort study supports the clinical importance of symptomatology, comorbidity burden, and prolonged severe neutropenia at the time of AIFS presentation. The composite clinical staging system may be useful for clinicians when counseling patients with AIFS and conducting clinical research.

Myeloprotection with trilaciclib in Chinese patients with extensive-stage small cell lung cancer receiving chemotherapy: Results from a randomized, double-blind, placebo-controlled phase III study (TRACES)

IntroductionTrilaciclib is a transient cyclin-dependent kinase 4/6 inhibitor that decreases the incidence of chemotherapy-induced myelosuppression in extensive-stage small cell lung cancer (ES-SCLC). TRACES study was designed to assess the safety, efficacy and pharmacokinetics (PK) of trilaciclib before chemotherapy in Chinese patients with ES-SCLC. MethodsThe study included an open-label safety run-in part (Part 1) and double-blinded, placebo-controlled part (Part 2) where patients received trilaciclib or placebo before chemotherapy. Treatment-naïve or previously treated ES-SCLC patients received intravenous trilaciclib (240 mg/m2) or placebo before etoposide/carboplatin or topotecan, respectively. Primary endpoints were PK, safety and duration of severe neutropenia (DSN) in Cycle 1 in Part 1 and Part 2. Exploratory endpoints included the effect of trilaciclib on other myeloprotection endpoints, safety and antitumor efficacy. ResultsOverall, 95 Chinese patients were enrolled, of which 12 and 83 patients were in Part 1 and Part 2, respectively. In Part 1, trilaciclib was well tolerated. Non-compartmental analysis results revealed no substantial differences in the main exposure parameters. In Part 2, 41 patients received trilaciclib, and 42 received placebo. Patients in trilaciclib arm vs placebo arm had a clinically and statistically significant decrease in DSN (mean [SD]) in Cycle 1 (0 [1.7] vs 2 [3.0] days; P = 0.0003), with improvements in additional neutrophil, red blood cell, and platelet measures. After a median follow-up of 14.1 months, the median overall survival was 12.0 months in trilaciclib arm and 8.8 months in placebo arm (HR, 0.69; 95 % CI: 0.40–1.22). Median progression-free survival was 4.8 months and 4.3 months, respectively (HR, 0.86; 95 % CI: 0.53–1.39). Trilaciclib had a well-tolerated safety profile. ConclusionsTrilaciclib in the Chinese population demonstrated a similar PK and safety profile as seen in other global trials. There was significant reduction of DSN in Cycle 1, thereby substantiating the myeloprotective effects of trilaciclib in Chinese ES-SCLC patients.

CAR-T Cell Therapy in Patients with Refractory Systemic Autoimmune Diseases Exhibits Less Inflammation, Toxicities and Different Cellular Dynamics Compared to Patients with B Cell Lymphoma

Chimeric antigen receptor (CAR) T-cell therapies have shown high efficacy in the treatment of B cell non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL) and are established as a standard treatment for patients with hematological malignancies. Aside from malignant B cells, autoreactive B cells can also cause great harm in patients with autoimmune diseases (AID), resulting in chronic inflammation, organ damage, and increased mortality. We have recently demonstrated that CD19-directed CAR-T cell therapy is feasible and effective in patients with refractory systemic lupus erythematosus (Mougiakakos et al, 2021; Mackensen et al., 2022), antisynthetase syndrome (Müller et al., 2023) and systemic sclerosis (Bergmann et al., 2023). Despite these promising data, there are many uncertainties in the treatment of AID patients with cellular therapies, which were primarily developed for the treatment of cancer patients. Here, we analyzed the occurrence and severity of toxicities, inflammatory markers, and the cellular dynamics of 15 AID patients and 40 NHL patients undergoing CAR-T cell therapy. All patients were treated in our center with either commercial CAR-T cell products (Axicabtagenee ciloleucel, Tisagenlecleucel, Lisocabtagen maraleucel) or with the investigational medicinal product MB-CART19.1 (in-house manufactured 2 nd generation anti-CD19 CAR-T cells with a 4.1BB co-stimulatory domain; Kretschmann et al., 2023). Average peak expansion was reached at day 7 in both patient groups. Despite comparable average peak levels, patients with AID showed lower incidence and severity of cytokine-release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS) compared to the NHL cohort. Consistent with reduced toxicity, AID patients received less tocilizumab and glucocorticoid treatment. Bone marrow toxicity with severe and/or prolonged cytopenia is a frequent long-term CAR-T cell related adverse event. Of interest, AID patients demonstrated a less profound decrease of neutrophils, platelet counts, and hemoglobin after CAR-T cell therapy compared to NHL patients and a faster recovery to normal values. Occurrence and duration of severe neutropenia (<500 neutrophils/µl) also differed between both patient cohorts. There was no late bone marrow toxicity in AID patients, whereas 19 of 40 patients with NHL showed at least one > grade 3 blood count reduction. In line with the Hematotox-Score predicting bone marrow toxicity, baseline inflammation (e.g. C-reactive protein, ferritin) prior to CAR-T cell treatment was higher in lymphoma patients than in AID patients. While AID patients quickly returned to normal ferritin values, elevated ferritin levels often persisted in the NHL cohort after CAR-T cell therapy. Given that AID patients showed fewer late toxicity and lower long-term inflammation, we speculated that persistence of CAR-T cells was lower. In line, longitudinal monitoring of the patient's immune cells including CAR-T cell kinetics demonstrated a typical contraction of CAR-T cell numbers with low-level persistence in both cohorts. We did not observe a difference in absolute CAR-T cell numbers or dynamics within the first three months after treatment. In contrast to NHL patients in remission, AID patients did not develop long-term persistence of CAR-T cells as most patients lost CAR-T cells within 1 year after cell infusion. Consistent with this observation, all AID patients showed B-cell reconstitution after loss of CAR-T cell persistence. Taken together, we observed less toxicities and severe adverse events in AID patients than in NHL patients despite similar CAR-T cell expansion and dynamics. The lack of CAR-T cell persistence and the early recurrence of B cells in AID patients is so far not explained and could provide novel insights in the biological processes controlling long-term CAR-T cell persistence.

Aggregation of human plasma and of human blood induced in vitro by pegfilgrastim originator formulation buffer and pegfilgrastim products

PEGylated recombinant human granulocyte colony stimulating factor (pegfilgrastim) is used clinically to reduce the incidence and duration of severe neutropenia in patients who have received chemotherapy treatment. Pegfilgrastim products are administered by subcutaneous injection. We herein report that solutions of pegfilgrastim originator product Neulasta®, of a biosimilar product candidate, and also of the pegfilgrastim originator formulation buffer, induced aggregate formation when mixed in vitro with human plasma, and formation of large membranous aggregated structures when mixed with human blood. Human donor variability in the plasma aggregation induced by pegfilgrastim products was observed. In all donors less aggregation occurred in plasma mixtures with the biosimilar pegfilgrastim product candidate compared to the originator products. Instantaneous aggregation of erythrocytes and formation of large membranous aggregated structures of erythrocytes occurred in mixtures of human blood with pegfilgrastim buffer or pegfilgrastim products. The formation of the large membranous aggregated structures likely involved fusion of erythrocyte membranes; erythrocyte membrane fusion events were observed. Pegfilgrastim proteins in the products accelerated the formation of irreversible erythrocyte aggregated structures. Pegfilgrastim originator formulation buffer (10 mM Na-acetate pH 4.0, 274 mM sorbitol, 0.004 % polysorbate 20) was identified as the main driver of the plasma and erythrocyte aggregation. Lipoprotein aggregation at low pH in the presence of sorbitol and erythrocyte membrane fusion induced by the lipoprotein aggregates, are proposed as the main mechanisms for the formation of plasma and blood aggregates. Such aggregation phenomena may also occur during pegfilgrastim clinical use and may be related to known side effects and individual variability in the efficacy of pegfilgrastim therapy.

Posaconazole and midostaurin in patients with FLT3-mutated acute myeloid leukemia: Pharmacokinetic interactions and clinical facts in a real life study.

Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Chemotherapy-induced neutropenia exposes these patients to a significant risk of invasive fungal infections (IFIs). International guidelines recommend primary antifungal prophylaxis with posaconazole (PCZ) but nested analysis of a phase III trial showed that strong PCZ inhibition of CYP3A4 diminished midostaurin metabolism and increased midostaurin plasma levels; however, midostaurin-related adverse events (AEs) were only moderately exacerbated. We conducted a prospective multicenter real-life study to evaluate (i) how often concerns around PCZ-midostaurin interactions made the hematologist prescribe antifungals other than PCZ, (ii) how remarkably PCZ increased midostaurin plasma levels, and (iii) how significantly PCZ-midostaurin interactions influenced hematologic and safety outcomes of induction therapy. Although the hematologists were blinded to pharmacokinetic findings, as many as 16 of 35 evaluable patients were prescribed antifungal prophylaxis with micafungin, weak CYP3A4 inhibitor, in place of PCZ (p < 0.001 for deviation from guidelines). In the 19 patients managed as per guidelines, PCZ-midostaurin interactions were more remarkable than previously characterized, such that at the end of induction therapy midostaurin minimum plasma concentration (Cmin ) was greater than three times higher than reported; moreover, midostaurin Cmin , maximum plasma concentration, and area under the curve were more than or equal to four times higher with PCZ than micafungin. Hematologic outcomes (complete remission and duration of severe neutropenia) and safety outcomes (midostaurin-related any grade or grade ≥3 AEs) were nonetheless similar for patients exposed to PCZ or micafungin, as was the number of breakthrough IFIs. In waiting for randomized phase III trials of new prophylaxis regimens, these findings show that PCZ should remain the antifungal of choice for the midostaurin-treated patient.

Assessing the Optimal Regimen: A Systematic Review and Network Meta-Analysis of the Efficacy and Safety of Long-Acting Granulocyte Colony-Stimulating Factors in Patients with Breast Cancer.

Patients with breast cancer undergoing chemotherapy are susceptible to prolonged and severe neutropenia. Multiple biosimilars of long-acting granulocyte colony-stimulating factors (LA-G-CSFs) have been newly developed to prevent this disease. Nonetheless, which LA-G-CSF regimen has the optimal balance of efficacy and safety remains controversial. Moreover, there is a lack of evidence supporting clinical decisions on LA-G-CSF dose escalation in poor conditions. PubMed, Embase, Cochrane Library, Web of Science, and several Chinese databases were searched (December 2022) to collect randomized controlled trials (RCTs) about LA-G-CSFs preventing chemotherapy-induced neutropenia in breast cancer patients. No restrictions were imposed on language. A Bayesian network meta-analysis was performed. We assessed the incidence of severe neutropenia (SN) and febrile neutropenia (FN), the duration of SN (DSN), and the absolute neutrophil account recovery time (ANCrt) for efficacy, while the incidence of severe adverse events (SAE) was assessed for safety. The study was registered in PROSPERO (CRD42022361606). A total of 33 RCTs were included. Our network meta-analysis demonstrated that lipegfilgrastim 6 mg and eflapegrastim 13.2 mg outperformed other LA-G-CSFs with high efficacy rates and few safety concerns (SUCRA of lipegfilgrastim 6 mg: ANC rt 95.2%, FN 97.4%; eflapegrastim 13.2 mg: FN 87%, SN 89.3%). Additionally, 3.6 mg, 4.5 mg, 6 mg, and 13.2 mg dosages all performed significantly better than 1.8 mg in reducing the duration of SN (3.6 mg: DSN, SMD -0.68 [-1.13, -0.22; moderate]; 4.5 mg: -0.87 [-1.57, -0.17; low]; 6 mg: -0.89 [-1.49, -0.29; moderate]; 13.2 mg: -1.02 [1.63, -0.41; high]). Increasing the dosage from the guideline-recommended 6 mg to 13.2 mg can reduce both the duration and incidence of SN (SMD -0.13 [-0.24 to -0.03], RR 0.65 [0.43 to 0.96], respectively), with no significant difference in SAE. For patients with breast cancer, lipegfilgrastim 6 mg and eflapegrastim 13.2 mg might be the most effective regimen among LA-G-CSFs. Higher doses of LA-G-CSF may enhance efficacy without causing additional SAEs.

Prevention of chemotherapy-induced neutropenia (CIN) with plinabulin (Plin) vs placebo (Plac) in patients (pts) with non-small cell lung cancer (NSCLC) treated with docetaxel (Doc): A pooled analysis from 3 randomized trials.

e21163 Background: CIN can lead to increased patient/healthcare burden, resource utilization, hospitalizations, and poorer quality of life (QoL). G-CSF has a high incidence of bone pain and mild thrombopenia and is given the day after chemo. Plin, a novel non-G-CSF small molecule, protects the bone marrow stem cell, has minimal bone pain, and protects platelet precursors. Plin is given on the same day as chemo and has NSCLC anticancer efficacy (ESMO 2021, Feinstein). The CIN effects of Doc plus Plin vs Doc with Plac were pooled from 3 NSCLC clinical trials. Methods: Data from randomized trials, phase (Ph) 3 trial 103 (NCT02504489), Ph2/3 trial 105 ( NCT03102606 ), and Ph2 trial 101 (NCT00630110) were pooled. Pts were randomized to either Doc (75mg/m2) plus Plin (20mg/m2 or its pharmacokinetic equivalent) (n = 146) or Doc plus Plac (n = 296). Doc was administered on day 1 of each 21-day cycle x 4 cycles, and Plin or Plac was administered ~30 minutes after Doc. Neutrophil counts were taken at predose and day (D) 8 of each cycle in studies 101 &amp; 103, and on predose, D1, 2, 6, 7, 8, 9, 10, 15, and 21 in study 105. Pts given G-CSF in D1-D3 were excluded. Duration of severe neutropenia (DSN) was calculated by methods previously reported (ASH 2022, Blayney). All Grade (Gr) and Gr4 neutropenia (N) rates, Absolute N count (ANC), febrile N (FN) rate, and ANC on D8 (‘nadir’) were obtained. QoL scores were obtained in studies 103 and 105 by EORTC QLQ-C30. Patient-reported adverse events (AEs) were collected. Results: Pt demographics were comparable. Plin was statistically and clinically significantly superior to Plac for All Gr and Gr4 N frequencies, Day 8 ANC (‘nadir’), and DSN (all had p &lt; 0.0001). Febrile Neutropenia (FN) and infection rates were numerically lower (see table). Fewer pts were treated with antibiotics among pts treated with Plin. Platelet count was unaffected with Plin; grade (gr) 3/4 thrombocytopenia was &lt; 1% with either Plin or Plac. The total frequency of treatment-emergent AEs for Plin vs Plac were 71% vs 80%. QoL scores were similar for Plin and Plac. Conclusions: In 3 independent randomized studies (101, 103, and 105), Plin demonstrated a superior benefit for CIN and showed clinical benefit for infection rate versus Plac. Additionally, Plin has the added benefits of pt convenience (same-day dosing and no additional visits or wearable device), a favorable safety and tolerability profile, anticancer efficacy, and QoL maintenance, which represents a distinct advantage over G-CSF. Clinical trial information: NCT02504489 ; NCT03102606 ; NCT00630110 . [Table: see text]

Real world outcomes of trilaciclib in ES-SCLC.

e20637 Background: Carboplatin, etoposide, and atezolizumab (PEA) is the most widely used combination for first-line treatment of extensive-stage small cell lung cancer (ES-SCLC). Chemotherapy-induced myelosuppression is a common sequalae that is traditionally managed with lineage-specific supportive care modalities. Studies that evaluated trilaciclib versus placebo in combination with chemotherapy demonstrated statistically significant improvements in the duration of severe neutropenia (SN), defined as ANC &lt; 500 cells/µL, in cycle 1 and incidence of SN as a result of its transient myeloprotective effects. There remains considerable controversy in the adoption of trilaciclib as a supportive medication in clinical practice. The objective of this quality assessment study was to assess utility of trilaciclib in real-world ES-SCLC patients. Methods: This was a single center study with quasi-experimental design comparing patients with confirmed ES-SCLC who received trilaciclib + PEA (PEAT) from April 2021 to July 2022 versus those who received PEA without trilaciclib (PEA) from February 2020 to February 2021. Patients with limited-stage SCLC, prior treatment with immunotherapies, carboplatin dose AUC &lt; 3.5 with cycle 1, and active clinical trial enrollment were excluded. The primary endpoint evaluated was incidence of SN after cycle 1 and during treatment period. Additional measures related to myelopreservation and patient outcomes were assessed as secondary endpoints. Demographic data was analyzed using descriptive statistics. Dichotomous and continuous variables were compared by Mann-Whitney U or one-sided Fisher’s exact test. Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier (KM) estimate. Results: 34 patients received PEAT and 44 patients received PEA. Demographic and baseline clinical characteristics were similar between both cohorts except for older median age of patients (69 years old vs 64 years old) and higher proportion of male patients (65% vs 39%) in the trilaciclib cohort. Even though there was a numerically lower rate of SN (3%) and hospitalization due to febrile neutropenia (FN) or infection (6%) in the PEAT versus the PEA (18%;11%) cohort, statistical significance was not met (p = 0.07;p = 0.065). Likewise, incidence of FN, platelet transfusion requirements, all-cause chemotherapy reductions, and treatment delays were not statistically different. However, the PEAT cohort as compared to PEA experienced a statistically significant reduction in red blood cell transfusion requirements (3% vs 23%; p = 0.02) and grade 3-4 anemia (6% vs 25%; p = 0.03). PFS and OS between the two cohorts were not statistically different. Conclusions: Based on this single center retrospective study, use of trilaciclib appears to confer improvement in the safety profile of PEA without negatively impacting survival outcomes. Therefore, results of this study support the integration of trilaciclib with PEA for ES-SCLC.

The CAR-Hematotox Score As a Prognostic Model of Toxicity and Response in Patients Receiving BCMA-Directed CAR-T for Relapsed/Refractory Multiple Myeloma

Introduction: Hematological toxicity and infectious complications are both common and substantially contribute to non-relapse mortality of CAR T-cell therapy. The recently developed CAR-HEMATOTOX (HT) score represents a validated risk-stratification system of hematotoxicity, infections, and clinical outcomes for R/R LBCL (Rejeski et al. Blood 2021/JITC 2022). The score integrates parameters of pre-CAR-T hematopoietic reserve (e.g. ANC, hemoglobin, platelet count) and inflammation (e.g. CRP, ferritin). Whether the HT score is of diagnostic utility in relapsed/refractory multiple myeloma (R/R MM) remains unclear. Methods: In this multicenter retrospective study, we characterized the influence of the HT score on toxicity and clinical outcomes in 102 patients receiving BCMA CAR-T with ciltacabtagene autoleucel (n=7) or idecabtagene vicleucel (n=95) in a standard-of-care setting across five international CAR-T centers. CRS and ICANS were graded according to ASTCT criteria. Neutrophil recovery phenotypes were defined as quick recovery vs. intermittent recovery vs. aplastic as previously described (Rejeski et al. Blood 2021). Early infection events (day 0-90) were defined as bacterial, viral or fungal based on microbiologic data or as a clinical syndrome of infection (e.g. pneumonia, cellulitis, cystitis) based on retrospective chart review. Severe (grade ≥3) infections were defined as requiring intravenous anti-infective agents and/or hospitalization. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) were compared using the log-rank test. Results: The baseline patient features were representative of R/R MM patients receiving BCMA CAR-T in a real-world setting: median age was 65 (range 39-81), median ECOG was 1 (interquartile range 0-1), median LDH was 200 U/L (IQR 173-240 U/L), and patients had received a median of 6 prior treatment lines (IQR 5-7). A total of 28% had high-risk genetic abnormalities (del17p, t(4;14), t(14;16)). Notably, the large majority of patients had received a prior autologous stem cell transplant (88.2%). On the last bone marrow (BM) assessment prior to CAR-T, greater than 5% clonal plasma cells were detected in 52% of patients. In terms of toxicity, the rate of severe (grade ≥3) CRS and ICANS was 4% and 8%, respectively. Tocilizumab was applied in 79/102 patients (77%); glucocorticoids were used in 43/102 patients (42%). The median CAR-HEMATOTOX score was 1 (IQR 1-3), including 46 HThigh and 56 HTlow patients. When comparing the risk groups, we found that HThigh patients more frequently exhibited BM plasma cell infiltration (59% vs. 34%, p=0.05). Serum LDH levels did not significantly differ by HT score (median 215 vs. 193 U/L, n.s.). The duration of severe neutropenia (ANC<500/µL) was significantly increased in HThigh patients compared to their HTlow counterparts (9 vs. 3 days, p<0.0001). The proportion of patients displaying aplastic neutrophil recovery was markedly increased in the HThigh group (Fig. 1A: 30 vs. 3%, p<0.001). The rate of severe CRS (9% vs. 0%, p=0.038) and severe ICANS (17% vs. 0%, p=0.001) was higher in HThigh patients, likely resulting in the increased use of glucocorticoids (57% vs. 30%, p=0.009). When studying infectious complications, we found that infections of any-grade were more common in the HThigh cohort (61% vs. 25%, p=0.0003). This was particularly evident for severe infections (39% vs. 3.6%, p<0.0001), including 2 fatal bacterial infections in HThigh patients. Overall, the increased toxicity burden observed in the HThigh cohort translated into a longer median duration of hospitalization (12 vs. 8 days, p<0.0001). Finally, a high HT score was associated with inferior PFS (Fig. 1B: 1-year PFS 80% vs. 27%, p<0.0001) and OS (1-yr OS 93% vs. 62%, p<0.0001). Conclusions: These findings emphasize the importance of baseline inflammatory state and hematopoietic function for the subsequent development of toxicity and early progression in patients receiving BCMA-directed CAR-T. The easy-to-use CAR-HEMATOTOX score enables early risk-stratification prior to lymphodepletion. Considering their overall low risk of severe toxicity, HTlow patients represent an attractive population to explore outpatient CAR-T application. On the other hand, patients with a high HT score likely benefit from intensified monitoring, anti-infective prophylaxis, early G-CSF, and awareness for a potential stem cell boost. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Biosimilar Versus Originator Pegfilgrastim for Preventing Chemotherapy-Induced Neutropenia: A Phase III Randomized, Multicenter, Evaluator-Blinded, Noninferiority Study.

PURPOSEThis study evaluated the efficacy, safety, and immunogenicity of biosimilar pegfilgrastim (PegFilBS) and originator pegfilgrastim (PegFilOR) in patients with stage 2-4 breast cancer.METHODSThis phase III randomized, multicenter, evaluator-blinded, noninferiority study recruited women with stage 2-4 breast cancer in Argentina who were scheduled to receive chemotherapy. Stratification was based on the breast cancer stage. The primary end point was the duration of severe neutropenia (DSN, noninferiority margin: 1 day) in the first chemotherapy cycle. Secondary end points assessed were incidence of severe neutropenia, grade 3 neutropenia, febrile neutropenia, infections, postchemotherapy hospitalization and duration, and the incidence of adverse drug reactions (ADRs).RESULTSA total of 120 patients were randomly assigned to receive PegFilBS (58 patients) or PegFilOR (62 patients). Severe neutropenia occurred in 52 of 283 cycles (18.4%) for 27 patients who received PegFilBS and in 48 of 297 cycles (16.2%) for 20 patients who received PegFilOR (P = .48). During the first cycle, severe neutropenia occurred in 16 patients who received PegFilBS (DSN: 0.78 ± 1.53 days) and in 11 patients who received PegFilOR (DSN: 0.53 ± 1.25 days; 95% CI, –0.26 to 0.76 days). In the intention-to-treat analysis, the mean DSN values were 0.90 ± 1.79 days for the PegFilBS group and 0.50 ± 1.21 for the PegFilOR group (95% CI, –0.15 to 0.95 days). No significant differences were observed for the secondary efficacy end points. Three patients experienced seven ADRs in the PegFilBS group while 10 patients experienced 31 ADRs in the PegFilOR group. The most common ADR was myalgia.CONCLUSIONRelative to PegFilOR, PegFilBS provided noninferior efficacy outcomes in Argentinian women with stage 2-4 breast cancer who were treated using myelosuppressive chemotherapy.

Comparison of Efficacy and Safety of Lupin’s Pegfilgrastim with Neulastim® as an Adjunct to Chemotherapy in Patients with Non Myeloid Malignancies: A Randomised Phase III Clinical Study

Introduction: Pegfilgrastim is indicated in patients receiving myelosuppressive anticancer drugs to reduce the Duration of Severe Neutropenia (DSN) and incidence of Febrile Neutropenia (FN). The efficacy and safety of a proposed pegfilgrastim biosimilar should be compared with an approved biologic drug to establish therapeutic equivalence. Aim: To compare the efficacy of Lupin’s biosimilar Pegfilgrastim versus Neulastim® (Amgen Inc.) as an adjunct to chemotherapy in patients with non-myeloid malignancies. Materials and Methods: The present prospective, open-label, randomised phase lll clinical study was conducted on a total of 170 patients with histologically or cytologically confirmed non-myeloid malignancies eligible to receive a myelosuppressive chemotherapy regimen. The participants were administered Lupin’s Pegfilgrastim (n=86) or Neulastim® (n=84) 6 mg by subcutaneous injection, once in each chemotherapy cycle for a maximum of three cycles. Patients were chemotherapy naive or had not received myelosuppressive chemotherapy within last 12 months of screening. The primary efficacy endpoint was DSN (number of days on which absolute neutrophil count &lt;0.5×109 /L) in cycle 1 of chemotherapy. Equivalence was confirmed if 95% Confidence Intervals (CI) were within the equivalence margin of ±1 day. Safety evaluation included assessment of Adverse Events (AEs), rate of discontinuation due to AEs, vital signs, and laboratory parameters. Statistical analysis were done using SAS Enterprise guide 9.4 (SAS Institute Inc., Cary, 2000). Results: Of the 170 patients balanced for demographic characteristics, 161 patients completed cycle 1, 151 patients completed cycle 2, and 142 patients completed cycle 3. The mean±Standard Deviation (SD) DSN in cycle 1 was 0.127±0.5533 days with Pegfilgrastim (n=63) and 0.197±0.6615 days with Neulastim® (n=66) in the Per Protocol (PP) assessment; and 0.174±0.636 days with Pegfilgrastim and 0.193±0.671 days with Neulastim® in the modified Intent-to-Treat (mITT) assessment. The mean DSN between the groups did not differ significantly (PP: p=0.5167, mITT: p=0.8554). The 95% CI of difference in mean DSN in PP (-0.2796 to 0.1481) and mITT (-0.2103 to 0.1889) assessments was contained within the predefined equivalence margin of ±1 day. Secondary outcomes and safety profiles were also comparable between the two groups. Conclusion: The present study establishes Lupin’s Pegfilgrastim as a therapeutically equivalent biosimilar alternative to Neulastim® in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy

The frequency, epidemiology and risk factors of bloodstream infections in febrile neutropenic patients with hematologic malignancies

Aim: Bacteremia is considered as the most significant cause of mortality and morbidity in febrile neutropenic patients. The epidemiology and risk factors might differ among institutions and over the time period. The aim of this study is to evaluate the frequency, epidemiology and factors predictive of bacteremia in neutropenic patients in a university hospital in Ankara between November 2007 and November 2008.&#x0D; Material and Methods: 177 febrile neutropenic episodes of 115 patients with hematological malignancies were included in this study. Cases were defined as patients with bloodstream infection and controls were the patients without bloodstream infections. We evaluated the cases and controls for the risk factors, complications and mortality rates. Microorganisms isolated from blood samples and their susceptibility patterns were also analysed.&#x0D; Results: The prevalence of bacteremia was 61%, 42.6% of them were catheter related and mortality rate was 12.4%. Bloodstream infections are more common in the patients with uncontrolled underlying disease and long term severe neutropenia. Duration of severe neutropenia (neutrophile count

Phase I/II study to assess the clinical pharmacology and safety of single ascending and multiple subcutaneous doses of PF-06881894 in women with non-distantly metastatic breast cancer

PurposeTo evaluate the pharmacodynamics (PD), pharmacokinetics (PK), and safety of single and multiple doses of PF-06881894 (pegfilgrastim-apgf; Nyvepria™), a biosimilar to reference pegfilgrastim (Neulasta®), in women with non-distantly metastatic breast cancer.MethodsIn Phase I (Cycle 0) of this Phase I/II study, the PD response (absolute neutrophil count [ANC]; CD34 + count), PK profile, and safety of a single 3- or 6-mg subcutaneous dose of PF-06881894 were assessed in chemotherapy-naïve patients before definitive breast surgery. In Phase II (Cycles 1–4), the PD response (duration of severe neutropenia [DSN, Cycle 1], ANC [Cycles 1 and 4]) and PK profile (Cycles 1 and 4) of single and multiple 6-mg doses of PF-06881894 concomitant with chemotherapy and after definitive breast surgery were assessed.ResultsTwenty-five patients (mean age 59 years) were enrolled (Cycle 0, n = 12; Cycles 1–4, n = 13). In Cycle 0, PD responses and PK values were lower with 3-mg versus 6-mg PF-06881894. In Cycles 1 and 4, mean DSN was 0.667 days after single or multiple 6-mg doses of PF-06881894, respectively. In Cycle 4 versus Cycle 1, PD responses were more robust; PK values (mean area under the curve, maximum concentration) were lower; and clearance values were higher. The safety profile of PF-06881894 was similar to that for reference pegfilgrastim.ConclusionPF-06881894 as a single 3- or 6-mg dose prior to definitive surgery, or multiple 6-mg/cycle doses postoperatively, with/without myelosuppressive chemotherapy, was consistent with the clinical pharmacology and safety profile of reference pegfilgrastim.Trial registrationOctober 2017. ClinicalTrials.gov Identifier: NCT02650193. EudraCT Number: 2015-002057-35.

Abstract CT116: Same-day administration of Eflapegrastim with chemotherapy enhances neutropenic recovery in neutropenic rats and in early-stage breast cancer patients

Abstract Background: Chemotherapy-induced neutropenia increases the likelihood of life-threatening infections. Currently, long-acting G-CSF products are administered 24 hours after chemotherapy (CT). Eflapegrastim's (Efla) greater marrow resident time should provide a pharmacodynamic advantage over pegfilgrastim (Peg), translating into a shorter duration of neutropenia (DN). The therapeutic potential of Efla, a long-acting G-CSF, was evaluated in a neutropenic rat model where neutropenia was induced via intraperitoneal docetaxel/cyclophosphamide. This study compared the DN with that of vehicle control and Peg at 0, 2, 5, and 24 hrs post-CT. We found that at all-time points, there was a marked reduction in the degree of neutropenia and a more rapid rate of absolute neutrophil count (ANC) recovery with Efla compared to Peg. When Efla was administered concomitantly with CT, ANC returned to normal within 12hrs for Efla vs 2.2 days post-nadir for Peg, while the DN in the vehicle group was 7 days. Pharmacokinetics (PK) of Efla for same-day dosing were similar to those reported for next-day dosing. Based on these results, a Phase 1 clinical trial is ongoing; results for the first 9 patients are reported. Material and Methods: Phase 1, open-label study where Efla is administered at a fixed dose of 13.2 mg at 0.5, 3, and 5 hours s.c. after the i.v. infusion of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) CT in patients with confirmed stage I-IIIA breast cancer. Patients &amp;gt;18 years, ECOG &amp;lt;2, adequate hematological, renal, hepatic function &amp; candidates for neoadjuvant or adjuvant CT were randomized 1:1:1 to Efla dose schedules. The primary endpoint was the duration of severe neutropenia (DSN) in Cycle 1. Secondary endpoints include incidence of Grade 3 febrile neutropenia (FN), PK &amp; safety in Cycle 1. Results: Nine patients (3 patients per cohort) were enrolled. Protocol defined dose-limiting toxicity was not met in any cohort. One patient each in the 3 hr and 5 hr cohorts, developed severe neutropenia and FN. The PK of Efla for patients in the same-day dosing cohorts were similar to those observed for next-day dosing, as predicted by neutropenic rat results. Conclusions: Results to date from both nonclinical and clinical studies were similar and support our hypothesis that the higher and more sustained marrow resident time of Efla appears to provide an effective prophylaxis against severe neutropenia when administered on the same day as CT. The 0.5 hour cohort of the study is being expanded to confirm these promising results. Citation Format: John A. Barrett, Shanta Chawla, Prasad S. Kolli, Yu- Yon Kim, Sri Lakshmikanthan, Meera Tugnait, Lyndah K. Dreiling, Francois Lebel. Same-day administration of Eflapegrastim with chemotherapy enhances neutropenic recovery in neutropenic rats and in early-stage breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT116.

A Phase 2, International, Multicenter, Prospective Clinical Trial of Subcutaneous Tbo-Filgrastim in Pediatric Patients with Solid Tumors Undergoing Chemotherapy

Background: Chemotherapy (CT)-induced neutropenia is a common complication from chemotherapy, limiting optimal dosing and treatment. Tbo-filgrastim (GRANIX®) is a non-glycosylated recombinant methionyl human granulocyte colony-stimulating growth factor manufactured by recombinant DNA technology. It is indicated to reduce the duration of severe neutropenia (SN) in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia (FN). It is approved under a biologic license application in the United States. This phase 2, multicenter, open-label study investigated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and immunogenicity of tbo-filgrastim in pediatric patients receiving at least 1 cycle of myelosuppressive CT.Methods: Patients ages 1 mo to <16 y with solid tumors without bone marrow involvement were administered tbo-filgrastim 5 µg/kg/body weight once daily subcutaneously. Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last CT treatment. Daily dosing with tbo-filgrastim continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 109/L but not longer than 14 consecutive days. Patients were stratified into three age groups: infants (1 mo to <2 y), children (2 to <12 y), and adolescents (12 to <16 y). The CT regimens included at least one of the following: etoposide, doxorubicin, ifosfamide, or cyclophosphamide. The primary endpoint was the safety of tbo-filgrastim; secondary objectives were to assess the PK, PD (incidence and duration of SN, defined as absolute neutrophil count <0.5x109/L), and efficacy (incidence of FN). Immunogenicity was also assessed.Results: Fifty patients (2 infants, 30 children, and 18 adolescents) were administered a single daily dose of tbo-filgrastim. The most common cancers were rhabdomyosarcoma (14%), neuroblastoma (14%), Ewing tumors (12%), and osteosarcoma (12%). The mean (SD) number of doses administered were 9.2 (2.83) in children and 7.3 (1.88) in adolescents. Twelve and 14 doses, respectively, were administered to each infant. Serious treatment-emergent adverse events (TEAEs) were reported in 24% of patients (Table). The most common serious TEAEs were FN (12%, 4 children, 2 adolescents), anemia (8%, 4 children) and thrombocytopenia (8%, 2 children, 2 adolescents), increased alanine aminotransferase (ALT) and increased aspartate aminotransferase (AST) (6% each). The majority of grade 3 and 4 events, per Common Terminology Criteria for Adverse Events (NCI CTCAE), were in the hematologic system organ class. Nine patients (18%) experienced treatment-related TEAEs. The most common treatment-related TEAEs were musculoskeletal and connective tissue disorders (4/50, 8%) and were of NCI CTCAE grade 1 severity. Two patients (2/50, 4%) had increases in liver function enzymes considered to be related to tbo-filgrastim and CT by the investigator. No clinical symptoms were observed with these events, which resolved by the end of the study. No deaths or study withdrawal occurred during the study. PK parameters of exposure were comparable between age groups as shown by the overlap of tbo-filgrastim serum concentrations (Figure). The incidence of SN was 52% (26/50; 95% CI 0.374-0.663). The mean (SD) duration of SN was 1.8 (2.21) d. The incidence of FN was 26% (13/50; 95% CI 0.146-0.403). Immunogenicity assessments found that none of the patients had an antidrug antibody response after tbo-filgrastim treatment.Conclusion: A daily dose of tbo-filgrastim 5 μg/kg/body weight administered to pediatric patients with solid tumors without bone marrow involvement demonstrated a safety profile consistent with the safety profile in adult patients. No immunogenic response was observed in this population. The increases in liver function enzymes were considered related to both tbo-filgrastim and CT by the investigator. The sponsor assessed these events to be related to CT and concomitant medications and not related to tbo-filgrastim. The incidence of FN was on the lower end of the range in the literature. PD variables of the incidence and duration of SN provide supportive results of the efficacy of tbo-filgrastim in pediatric cancer patients. [Display omitted] DisclosuresBias:Teva ratiopharm: Employment, Equity Ownership. Lammerich:Teva ratiopharm: Employment, Equity Ownership. Roth-Ben Arie:Teva Pharmaceuticals Industries: Employment. Zou:Teva Pharmaceuticals: Employment, Equity Ownership. Buchner:Teva ratiopharm: Employment, Equity Ownership.

Comparison of Immunogenicity between the Proposed Pegfilgrastim Biosimilar MYL-1401H and Reference Pegfilgrastim

Introduction: Pegfilgrastim, a long-acting granulocyte colony-stimulating factor (G-CSF), is indicated for reduction of incidence of febrile neutropenia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy. Here, the immunogenicity data for MYL-1401H, a proposed biosimilar of pegfilgrastim, from the clinical studies will be presented.Methods: The efficacy, safety, and immunogenicity of MYL-1401H were investigated in 3 clinical studies, 2 in healthy volunteers (HV) and 1 in patients receiving chemotherapy. MYL-1401H-1001 was a 3-way crossover study comparing the pharmacokinetics (PK) and pharmacodynamics (PD) of a single 2-mg dose of MYL-1401H with reference pegfilgrastim (Neulasta®) sourced from both the European Union (EU) and United States (US) in HV. MYL-1401H-1002 was a parallel-group study designed to compare the immunogenicity of MYL-1401H with US-pegfilgrastim at a repeated 6-mg dose in HV. MYL-1401H-3001 was a multicenter, randomized, double-blind, parallel-group equivalence study of MYL-1401H 6 mg vs EU-pegfilgrastim 6 mg in patients with breast cancer receiving chemotherapy for 6 cycles. The primary efficacy endpoint in MYL-1401H-3001 was duration of severe neutropenia in cycle 1, defined as days with absolute neutrophil count <0.5 × 109/L. A thorough assessment of immunogenicity was conducted across the 3 studies. The antidrug antibody (ADA; Covance, Chantilly, VA) analysis was performed using a validated, sensitive, and specific analytical method on the MesoScale Discovery® Platform (Rockville, MD). Serum samples were analyzed for the presence of ADA against MYL-1401H, EU-pegfilgrastim, and US-pegfilgrastim. Samples that resulted positive in the screening assay were further evaluated in a confirmatory assay. The samples confirmed as ADA positive were titrated to elucidate relative levels of the ADA response and further evaluated for domain characterization to determine if the antibodies were specifically directed against the polyethylene glycol (PEG) or the G-CSF domain of the molecule, or both. Samples confirmed as positive for ADA were analyzed for neutralizing antibodies (NAb; CIRION BioPharma Research) using a validated cell-based assay.Results: Overall, these studies demonstrated that the PK, PD, efficacy, and safety of MYL-1401H were equivalent to reference pegfilgrastim. Across all 3 studies, the proportions of subjects who were ADA positive before dosing were similar in the MYL-1401H (30/223; 13.5%) and EU-pegfilgrastim groups (16/139; 11.5%) and were lower in the US-pegfilgrastim group (4/97; 4.1%). Most (86.0%) of the subjects with ADA had antibodies that recognized the PEG domain, which may be attributable to exposure to PEG-related compounds in the environment as well as the highly sensitive nature of the assay, which can detect very low levels of antibodies. Treatment-induced impact on immunogenicity across the 3 studies was evaluated by analyzing the postdose ADA results excluding those subjects who were ADA positive at baseline (Table). Overall, the proportions of subjects with postdose treatment-induced ADA were similar in the MYL-1401H (20/192; 10.4%) and EU-pegfilgrastim groups (17/123; 13.8%), while they were higher in the US-pegfilgrastim group (28/93; 30.1%). Although the proportion of subjects with treatment-induced ADA was higher in the US-pegfilgrastim group, in most cases, the ADA recognized only the PEG moiety, the titers were low, and the antibodies were non-neutralizing. Two subjects (1 each in the MYL-1401H and EU-pegfilgrastim groups) had antibodies against the G-CSF moiety only. Two subjects were NAb positive in the MYL-1401H group, while none were NAb positive in either reference pegfilgrastim group. There was no evidence of loss of efficacy or severe treatment-induced immune-related adverse events in ADA- or NAb-positive subjects.Conclusion: Results in HV indicate that MYL-1401H does not induce either early or late immune response and has a low immunogenic potential, similar to that of EU- and US-pegfilgrastim, after repeated administration in a sensitive population without any confounding illness or immunosuppressive medications. Similarly, the immunogenic potentials of MYL-1401H and EU-pegfilgrastim are low in patients with breast cancer. Overall, MYL-1401H has an immunogenic profile similar to that of EU-pegfilgrastim and US-pegfilgrastim. [Display omitted] DisclosuresWaller:Mylan: Consultancy, Honoraria. Ranganna:Mylan Pharmaceuticals Inc: Employment. Pennella:Mylan: Employment. Mattano:HARP Pharma Consulting, LLC: Employment. Loa:Mylan Pharmaceuticals Inc: Employment. Donnelly:Mylan Pharmaceuticals Inc: Employment. Liu:Mylan Pharmaceuticals Inc: Employment. Watson:Covance: Employment. St-Jean:CIRION BioPharma Research Inc: Employment. Chatterjee:Biocon Research Ltd: Employment. Nayak:Biocon Research Ltd: Employment. Sengupta:Biocon Research Ltd: Employment. Kothekar:Biocon Research Ltd: Employment. Barve:Mylan Pharmaceuticals Inc: Employment.

Head-to-head comparison of single agent (SA) plinabulin (Plin) versus pegfilgrastim (Peg) for the prevention of chemotherapy-induced neutropenia (CIN) in the phase 3 trial PROTECTIVE-1.

547 Background: Peg is the current standard of care (SoC) for the prevention of CIN, with a low absolute neutrophil (N) count (ANC) week 1 after chemotherapy (chemo) with normalization in week 2. Breakthrough designation agent from FDA, Plin, a novel, non-G-CSF agent for the prevention of CIN, produces a normal ANC in week 1 of cycle (C) 1 by potentially protecting progenitor cells in bone marrow from chemo assault, and also has anticancer activity (Blayney, St Gallen 2019; ASCO 2019). Here we report data from a pre-specified interim analysis from PROTECTIVE-1 (Study 105; NCT03102606). Methods: Breast cancer (BC), lung (NSCLC) and prostate cancer (HRPC) pts with at least 1 risk factor as per NCCN, received docetaxel (Doc) 75 mg/m2 with either Peg 6mg (n=53) or Plin 40 mg (n=52) over 4 cycles, and had ANC blood draws on Day (D) 1, 2,6,7,8,9,10,15 in C1 (Covance Central Laboratory). Plin was given on D1, as a 30 min IV infusion, 30 min after Doc, and Peg, 24 hrs after Doc. Primary objective was to demonstrate non-inferiority (NI) of SA Plin vs SA Peg for duration of severe neutropenia (DSN) in C1. NI of Plin vs Peg would be declared if the upper limit of 95% confidence interval for the mean DSN difference between Plin and Peg would be &lt;0.65 day. Other endpoints included C1 platelet count, C1 bone pain scores (validated questionnaire), C1-4 clinical sequelae of CIN through [febrile neutropenia (FN), infection, antibiotic and hospitalization rate, and Doc discontinuation (Discont) and delays], and safety (AEs, hematology and chemistry, vital signs) Results: Predefined DSN NI criterion between SA Plin and SA Peg was met. C1 Grade 4 toxicity was not different between Plin and Peg (p=NS). Clinical sequelae of CIN were comparable or slightly better for Plin vs Peg (see Table). Plin caused less bone pain (p=0.01) and less thrombocytopenia (p&lt;0.0001 on D15) vs Peg. AE frequency and overall safety was comparable for SA Plin and SA Peg. Conclusions: SA Plin has efficacy for Doc CIN prevention non-inferior compared to SoC Peg, and accordingly has comparable (or numerically better) profile for clinical sequelae of CIN. Plin has an advantage for bone pain, platelet counts, convenience of use (same day vs next day dosing) over SoC Peg and has anticancer activity. Clinical trial information: NCT03102606. [Table: see text]

Clinical trial testing superiority of combination plinabulin (Plin) and pegfilgrastim (Peg) versus peg alone in breast cancer treated with high-risk febrile neutropenia risk chemotherapy (chemo): Final results of the phase 3 protective-2 in chemo-induced neutropenia (CIN) prevention.

533 Background: Peg is standard of care (SoC) for the prevention of CIN. Peg’s mechanism of action leaves patients vulnerable to FN in week 1 of the chemo cycle(C), as the absolute neutrophil count (ANC) does not normalize until week 2. Plin is a first-in-class, non-G-CSF small molecule agent, which received breakthrough designation from FDA in CIN. It prevents CIN by protecting progenitor cells in bone marrow from chemo assault and has normal ANC in week 1 (Blayney JAMA Onc 2020). Phase 2 testing showed the combination of Plin and Peg achieved CIN protection throughout the entire cycle vs Peg alone (Blayney: St Gallen 2019, ASCO 2019). Methods: Plin is given on Day (D)1 after Chemo, has a favorable safety profile, and also has anticancer activity. A separate phase 3 study evaluating Plin as an anticancer agent (DUBLIN-3; NCT02504489) in NSCLC pts is underway, with anti-cancer results in OS expected in 2021. In PROTECTIVE-2 (Study 106; NCT0329457), we added Plin (on D1) to Peg (on D2), testing superiority of the combination for CIN prevention vs Peg alone. Study 106, is a global multicenter randomized (1:1) double-blind study to evaluate Plin 40 mg + Peg 6mg (Arm 1) versus Peg 6mg + Placebo (Plac) (Arm 2) in preventing Severe Neutropenia (N), (defined as ANC &lt;0.5 cells × 10E9/L) in early-stage BC (node positive or node negative with a high risk of recurrence) pts. 221 pts with ECOG status 0 or 1 received Docetaxel (75 mg/m2), Doxorubicin (50 mg/m2), and Cyclophosphamide (500 mg/m2) (TAC) on D1 for four 21 D cycles and study treatment. Central laboratory ANC was assessed at Covance in Cycle 1 (C1) on D 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, and 15. Primary objective was to compare the percentage (%) of pts with a Duration of Severe Neutropenia (DSN) of 0 days [that is % of pts with no Grade (Gr) 4 neutropenia (N)] in C1 in each arm. Key secondary endpoints were DSN and ANC Nadir in C1. We also evaluated safety (AE frequency and Grade). Conclusions: Adding Plin to Peg offers superior CIN protection compared to Peg alone and also has a superior safety profile by lowering over 20% of grade 4 AE. The effect size of the CIN protection in the combination is also correlated to clinical meaningful FN reduction compared to peg alone. Clinical trial information: NCT03531099. [Table: see text]

Effects of Trilaciclib on Chemotherapy-Induced Myelosuppression and Patient-Reported Outcomes in Patients with Extensive-Stage Small Cell Lung Cancer: Pooled Results from Three Phase II Randomized, Double-Blind, Placebo-Controlled Studies

BackgroundChemotherapy-induced myelosuppression (CIM) and its sequalae cause significant side effects and harm to quality of life. Trilaciclib is an intravenous CDK4/6 inhibitor that is administered prior to chemotherapy to protect hematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection). Patients and MethodsData from three randomized, double-blind, placebo-controlled studies (NCT02499770, NCT03041311, and NCT02514447) were pooled to evaluate the effects of trilaciclib administered prior to standard-of-care chemotherapy (first-line etoposide plus carboplatin [E/P], first-line E/P plus atezolizumab, and second-/third-line topotecan) in patients with extensive-stage small cell lung cancer (ES-SCLC). The primary endpoints were duration of severe neutropenia (absolute neutrophil count < 0.5 × 109 cells/L) in cycle 1 and occurrence of severe neutropenia. Additional prespecified endpoints further assessed the effect of trilaciclib on myeloprotection, health-related quality of life (HRQoL), antitumor efficacy, and safety. ResultsOf 242 randomized patients, 123 received trilaciclib and 119 received placebo. Compared with placebo, administration of trilaciclib prior to chemotherapy resulted in significant decreases in most measures of multilineage CIM. The reduction in hematologic toxicity translated into the reduced need for supportive care interventions and hospitalizations due to CIM or sepsis and improvements in HRQoL domains related to the protected cell lineages, including fatigue, physical wellbeing, and functional wellbeing. Antitumor efficacy was similar for patients receiving trilaciclib or placebo. ConclusionAdministering trilaciclib prior to chemotherapy resulted in clinically meaningful reductions in CIM and its consequences and improved patient HRQoL, with no impact on the antitumor efficacy of three individual chemotherapy regimens used in the first- or second-/third-line treatment of ES-SCLC.

Abstract OT-06-01: Open-label, phase 1 study to evaluate duration of severe neutropenia after same-day dosing of eflapegrastim in patients with breast cancer receiving docetaxel and cyclophosphamide (NCT04187898)

Abstract Background: Eflapegrastim (Rolontis®, Efla) is a long-acting granulocyte-colony stimulating factor (G-CSF), consisting of a recombinant human G-CSF analog conjugated to a human IgG4 Fc fragment via a short polyethylene glycol linker. Efla is not a biosimilar and represents the first myeloid growth factor innovation in more than 15 years. In preclinical studies with chemotherapy-induced neutropenic rats, Efla showed ~3-fold higher exposure in serum and higher exposure in bone marrow at similar doses compared to pegfilgrastim (Peg). The duration of neutropenia (DN) was shown to be significantly shorter with Efla vs Peg when administered on the same day and 24-hours post-chemotherapy. Additionally, the DN after Efla administered on the same day as chemotherapy was similar to the DN 24 hours post-chemotherapy. Moreover, in two Phase 3 studies that randomized a total of 643 patients with early-stage breast cancer (ESBC) to either Efla (3.6 mg G-CSF n=314) or Peg (6 mg G-CSF n=329) given ~ 24 hours after docetaxel and cyclophosphamide (TC) administration, the duration of severe neutropenia (DSN) was statistically noninferior in patients treated with Efla compared to Peg. As a standard of practice, G-CSF products require administration 24 hours after chemotherapy. Since Efla preclinical and clinical results suggest that the increased activity of Efla may provide effective prophylaxis against chemotherapy-induced neutropenia when administered on the same day as chemotherapy, the purpose of this study is to assess the feasibility of Efla same-day (3 different dosing timepoints) in patients receiving TC for treatment of ESBC. Trial Design: This is a randomized, schedule finding, multicenter, Phase 1, open-label study evaluating the same-day administration of 13.2 mg/0.6 mL Efla (3.6 mg G-CSF) following IV infusion of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) in patients with ESBC. Patients will be randomized 1:1:1 to Efla dose schedules of 0.5, 3, and 5 hours after TC. The primary endpoint is DSN (ANC &amp;lt;0.5×109/L) in Cycle 1. The secondary endpoints for Cycle 1 administration include the incidence of SN, time to recovery from SN, incidence of Grade 3 febrile neutropenia, incidence of neutropenic complications, and pharmacokinetics (PK) of Efla. Blood for hematology will be drawn daily for the first 10 days and then on Day 1 of Cycles 2-4. Eligibility Criteria: This study is enrolling histologically confirmed (operable stage I-IIIA) patients with ESBC, who are &amp;gt;18 years of age, are candidates for neoadjuvant or adjuvant TC chemotherapy, have an ECOG of &amp;lt;2, with adequate hematological, renal, and hepatic function. Patients will be excluded if they have a known sensitivity or previous reaction to E. coli derived products, exposure to a G-CSF agent within 3 months, history of bone marrow or hematopoietic stem cell transplant, radiotherapy or surgery within 30 days, are pregnant, or are breast-feeding. Statistical Methods: A sample size of 15 patients per dosing schedule arm was determined to provide adequate precision for the 95% CI of the DSN and secondary endpoints, including PK parameters. The sample size produces a 2-sided 95% CI with a distance from the mean DSN to the limits that is equal to 0.554 using t-distribution when the estimated standard deviation is 1.0 days. A safety evaluation will be performed once the first three patients in each arm have completed Cycle 1. Target Accrual: 45 patients (15 subjects/arm). Enrollment began in April 2020. Citation Format: Lee S. Schwartzberg, Jawad Francis, Hlalah Osama, Manuel Modiano, Jayaram Bharadwaj, Shanta Chawla, Gajanan Bhat, Francois Lebel, Nishan Tchekmedyian. Open-label, phase 1 study to evaluate duration of severe neutropenia after same-day dosing of eflapegrastim in patients with breast cancer receiving docetaxel and cyclophosphamide (NCT04187898) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-06-01.